Consumption of human milk is one of the most cost-effective strategies known to medicine for protecting infants against morbidity and mortality due to infectious disease. Human milk may be considered a natural and efficacious “nutriceutical,” i.e., a model food that conveys immunologic benefits. Protection against infectious diseases occurs through a variety of complementary mechanisms found in human milk, including oligosaccharides and their related glycoconjugates. Significantly enhanced immunologic protection by breastfeeding has been demonstrated for diarrheal diseases, respiratory tract illnesses, bacteremia, meningitis, and necrotizing enterocolitis. Protection by breastfeeding is especially efficacious against diarrheal disease.
Milk oligosaccharide structures are thought to serve as receptor analogs that can inhibit pathogen binding to host ligands (1-3). It appears that certain α1,2-linked fucosylated oligosaccharides in human milk are associated with protection against diarrhea due to campylobacter (2,4), caliciviruses (3-5), and stable toxin (ST)-associated Escherichia coli (1,6,7).
Oligosaccharides and their related glycoconjugates are major components of the innate defense system found in human milk. Oligosaccharides, which vary from 3 to 32 sugars in size, constitute the third-most common solid component of human milk after lactose and lipid, but their role is immunologic rather than nutritive. Oligosaccharides appear to have several different immunologic functions. Several types of oligosaccharides, including fucosyloligosaccharides, sialylated oligosaccharides, and non-fucosylated non-sialylated oligosaccharides in human milk, have prebiotic properties, i.e., selective stimulation of the growth of beneficial bacteria in the intestine. Importantly, protection against specific pathogens has been described for both fucosylated and sialylated human milk oligosaccharides (5, 6, 24, 27, 28). Both the fucosylated oligosaccharides and the sialylated oligosaccharides may have structural homology to cell receptors for enteropathogens and inhibit pathogen binding by blocking binding to relevant cell receptors (24, 29, 30). Certain pathogens are thought to bind to sialic acid- and fucose-containing receptors, including enteropathogenic Escherichia coli (EPEC), rotavirus, Haemophilus influenzae and other pathogens (30-33). In addition to the unbound oligosaccharides, protection by glycoconjugated substances in human milk has been demonstrated by in vitro studies and/or animal models against labile toxin and cholera toxin, heat-stable enterotoxin of E. coli (ETEC), campylobacter, shiga toxin, Streptococcus pneumoniae and rotavirus (16, 17, 24, 34). Lactadherin, a 46-kDa glycoprotein, has been found to vary in concentration in human milk, and significant protection against symptomatic rotavirus infection is associated with increasing concentrations of lactadherin in maternal milk (34).
The fucose terminus of oligosaccharide structures may be connected by an α1,2 linkage catalyzed by a fucosyltransferase produced by the secretor gene (FUT2) or by the fucosyltransferase I gene (FUT1), or by an α1,3 or α1,4 linkage catalyzed by fucosyltransferases produced by the Lewis gene (FUT3) family. Polymorphisms of the secretor and Lewis genes are known to determine expression of the Lewis blood group type, fucosylated oligosaccharide patterns in human milk, and histo-blood group antigens on human epithelial cell surfaces (21, 22, 35). Some individuals are non-secretors (i.e., homozygous recessive for the secretor gene) who do not synthesize α1,2-linked fucosyloligosaccharides in their secretions. In Indo-European and African populations, the prevalence of non-secretors is approximately 20%, while in some other populations, such as Mexicans of indigenous ancestry, non-secretors are much less common (36-38). In certain cases it has been shown that this heterogeneity of expression is associated with differential risk of infectious diseases in individuals and populations (5, 6, 28, 37, 39-44). Moreover, variation in concentration of protective oligosaccharides in human milk may result in breastfed infants with differing levels of protection against specific infectious diseases (21, 22, 36, 39, 45).
The most common oligosaccharides of human milk include four α1,2-linked fucosylated oligosaccharides (lacto-N-fucopentaose I [LNF-I], 2-fucosyllactose [2′-FL], lacto-N-difucohexaose I [LDFH-I] and lactodifucotetraose [LDFT]); three fucosylated oligosaccharides that lack 2-linked fucose (lacto-N-fuco-pentaose II [LNF-II], 3-fucosyllactose [3-FL], and lacto-N-fucopentaose III [LNF-III]); and their two precursors (lacto-N-tetraose [LNT] and lacto-N-neotetraose [LNneoT]). These nine oligosaccharides are homologs of the Lewis histo-blood group antigens, respectively: H-1, H-2, Leb, Ley, Lea, Lex, type 1 precursor, and type 2 precursor. The most commonly occurring specific α1,2-linked fucosylated oligosaccharide in human milk is 2′-FL (H-2 epitope). Comparing the composition of milks from many different mammalian species, 2′-FL is also the most conserved oligosaccharide structure, suggesting its importance in evolutionary biology (46). 2′-FL is absent, however, from the milk of some species, including cow's milk.